Abstract

Lipoxygenases (LOXs) are iron‐containing enzymes that catalyse the peroxidation of polyunsaturated fatty acids. In mammals,
LOX products and their metabolites are potent lipid mediators that provoke diverse biological responses. These eicosanoids,
derived from arachidonic acid, play important roles in inflammation and the resolution of inflammation. Moreover, they have
been implicated in the development of cardiovascular disease. Although several LOX isoforms are expressed in individual organisms,
each generates a specific product. How structurally and mechanistically related enzymes generate different products from a
common substrate is not fully understood. In addition, the biological effects of many of the lipid mediators produced through
LOX pathways remain to be uncovered.

Key Concepts:

Arachidonic acid is a substrate for lipoxygenases, iron enzymes that catalyse the peroxidation of polyunsaturated fatty acids.

Mammalian lipoxygenases transform the common substrate (arachidonic acid) to a unique stereo‐ and regiospecific product.

Leukotriene synthesis is initiated by 5‐lipoxygenase.

Lipoxygenase products and their downstream metabolites are potent signalling molecules, some of which play roles in inflammation
or its resolution.

Lipoxygenase products are associated with cardiovascular diseases, but their molecular mechanism of action remains unclear.

Stable 5‐LOX. The N‐terminal domain is in blue, and the catalytic domain in green with helix α2 as positioned in 5‐LOX (solid ribbon) and 15‐LOX (2P0M) in transparent ribbon. The catalytic Fe is shown as a rust coloured sphere.

Figure 2.

Lipid mediators derived from AA. A total of 12 isomers of HPETE can be derived from AA, four from the reaction centred at each of three pentadienes. Enzymes that initiate the reaction at C7 (red), C10 (blue)
and C13 (green) are 5‐LOX, 12‐LOX and 15‐LOX, respectively.

FLAP and LTC4 synthase. (a) Cartoon rendering of a FLAP trimer (pdb 2QZM), protomers are in distinct colours. An iodinated analogue of the inhibitor MK‐591 is depicted in sphere
rendering (C, light blue; O, red; N, blue and I, deep purple). (b) A superposition of an LTC4 synthase protomer (green) (pdb 2UUH) onto FLAP. The GSH is in sphere rendering (C, magenta and S, orange) as well as a detergent molecule (C, green and O, red), which is presumed
to indicate the binding site for LTA4. The stick rendering is MK‐591.

Martinez Molina D, Eshaghi S and Nordlund P (2008) Catalysis within the lipid bilayer‐structure and mechanism of the MAPEG family of integral membrane proteins. Current Opinion in Structural Biology 18(4): 442–449.